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Biodegradable polymers: an update on drug delivery in bone and cartilage diseases.

31 Jul 2019-Expert Opinion on Drug Delivery (Taylor & Francis)-Vol. 16, Iss: 8, pp 795-813

TL;DR: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases and will review their applications in osteoporosis, inflammatory arthritis, cancer and bone and cartilage tissue engineering.
Abstract: Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to those connective tissues very challenging. Consequently, effective and targeted delivery for bone and cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for a targeted and temporal controlled release of one or more drugs in concentrations within the therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously promote the in situ tissue repair. Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteoporosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and cartilage tissue engineering. Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of diseases, biomarkers, and targets as well as the development of innovative tools has led to the design of high value-added DDS. However, some challenges persist and are mainly related to an appropriate residence time and a controlled and sustained release over a prolonged period of time of the therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders the translation of many formulations into the clinical practice.
Topics: Targeted drug delivery (57%), Drug delivery (52%)

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Expert Opinion on Drug Delivery
ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20
Biodegradable polymers: an update on drug
delivery in bone and cartilage diseases
Ana Cláudia Lima, Helena Ferreira, Rui L. Reis & Nuno M. Neves
To cite this article: Ana Cláudia Lima, Helena Ferreira, Rui L. Reis & Nuno M. Neves (2019):
Biodegradable polymers: an update on drug delivery in bone and cartilage diseases, Expert
Opinion on Drug Delivery, DOI: 10.1080/17425247.2019.1635117
To link to this article: https://doi.org/10.1080/17425247.2019.1635117
Accepted author version posted online: 20
Jun 2019.
Published online: 31 Jul 2019.
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REVIEW
Biodegradable polymers: an update on drug delivery in bone and cartilage diseases
Ana Cláudia Lima
a,b
, Helena Ferreira
a,b
, Rui L. Reis
a,b,c
and Nuno M. Neves
a,b,c
a
3Bs Research Group, I3Bs Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal;
b
ICVS/
3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal;
c
The Discoveries Centre for Regenerative and Precision Medicine,
Headquarters at University of Minho, Guimarães, Portugal
ABSTRACT
Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to
those connective tissues very challenging. Consequently, effective and targeted delivery for bone and
cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for
a targeted and temporal controlled release of one or more drugs in concentrations within the
therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously
promote the in situ tissue repair.
Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegrad-
able biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteo-
porosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and
cartilage tissue engineering.
Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of
diseases, biomarkers, and targets as well as the development of innovative tools has led to the design
of high value-added DDS. However, some challenges persist and are mainly related to an appropriate
residence time and a controlled and sustained release over a prolonged period of time of the
therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders
the translation of many formulations into the clinical practice.
ARTICLE HISTORY
Received 31 March 2019
Accepted 19 June 2019
KEYWORDS
Bone diseases; cartilage
diseases; biodegradable
polymers; drug delivery
systems; controlled drug
release; targeted drug
delivery; tissue engineering
1. Introduction
Bone and cartilage-related diseases affect the musculoskeletal
system and function, leading to a significant burden over the
global public health and economy [1]. The most common
disorders involving those connective tissues include osteo-
porosis, inflammatory arthritis (e.g. osteoarthritis OA and
rheumatoid arthritis RA), cancer, trauma and defects [2].
Due to the increasing age of the global population, the
World Health Organization has predicted a rapid growth of
these clinical conditions [3]. The pain and impaired physical
condition associated with those diseases generally lead to
mental health problems, increased risk of development of co-
morbidities and, consequently, of mortality. Moreover,
impaired musculoskeletal health is responsible for the greatest
loss of productive life years in the workforce and for large
amounts of money spent in their treatment.
Despite the significant occurrence of bone and cartilages
diseases, their effective treatments remain a challenge mainly
due to their peculiar and highly organized structures [4]. Bone
is a vascularized biomineralized connective tissue, composed
of oriented collagen I fibers and nanocrystals of hydroxyapa-
tite, as well as of proteoglycans and glycoproteins [5]. The
hierarchical structure ranging from nanoscale to macroscale
ensures the high mechanical strength and structural complex-
ity needed to support the force applied to those tissues.
Indeed, it is a multifunctional organ that is reinforced by
osteogenic cells, such as osteoblasts and osteoclasts, but also
harbors hematopoietic stem cells and mature immune cells,
including B cells and macrophages, in the bone marrow.
Therefore, bone cells are toughly connected to immune cells,
sharing a variety of molecules, including cytokines, hormones,
surface receptors and transcription factors [6]. Those interac-
tions are crucial to maintain the physiological processes but
can also be responsible to induce pathological conditions.
Indeed, despite the ability of self-repair of bone, in elderly
patients or in the presence of large defects or congenital
abnormalities its regeneration is compromised. Unlike bone,
cartilage is an avascular and aneural tissue consisting of col-
lagen type II, proteoglycans (mainly aggrecan), hyaluronic acid
and other glycosaminoglycans (GAGs) [7]. The highly orga-
nized network of collagen and GAGs fibrils surrounds the cell
type characteristic of cartilage, the chondrocytes.
Consequently, in response to injury, cartilage has limited
intrinsic ability to self-repair. Thus, in order to prevent irrever-
sible or at least to minimize the extent of joint damage, rapid
diagnosis and initiation of treatment is required.
In the last years, the increased knowledge of the physio-
pathology of cartilage and bone diseases led to a dramatic
change in the available treatment modalities. Therefore, the
term drug in this review is not limited to the conventional
therapeutic agents commonly used (e.g. anti-inflammatory,
CONTACT Rui L. Reis rgreis@i3bs.uminho.pt; Nuno M. Neves nuno@i3bs.uminho.pt 3Bs Research Group, I3Bs Research Institute on Biomaterials,
Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal
EXPERT OPINION ON DRUG DELIVERY
https://doi.org/10.1080/17425247.2019.1635117
© 2019 Informa UK Limited, trading as Taylor & Francis Group

antibiotic and anti-cancer drugs), including also recombinant
proteins and genes. Recombinant proteins are used as highly
effective medical treatments for a wide range of diseases in
which a protein is either lacking or present in an insufficient
amount (e.g. transforming growth factor TGF and bone
morphogenetic proteins BMP) or is abnormally highly
expressed (e.g. antibodies to neutralize the excess pro-
inflammatory cytokines) [8]. Consequently, therapeutic pro-
teins can include antibodies, hormones, growth factors, antic-
oagulants, blood factors, enzymes, Fc fusion proteins,
interferons, interleukins, and thrombolytic drugs, which are
been produced by recombinant DNA technology. If the
recombinant proteins are intended to activate or suppress
the activity of the immune system, the treatment is referred
to as immunotherapy or biological therapy [9]. In inflamma-
tory diseases, such as OA and RA, immunotherapies aim to
suppress/reduce the immune system activity (e.g. by neutraliz-
ing pro-inflammatory cytokines and by binding and blocking
receptors that trigger immune cells activation) or to eliminate
and regulate immune cells that contribute to tissue damage
(e.g. effector lymphocytes). Conversely, in cancer immunother-
apy, the goal is to harness and direct the immune mechanisms
to eradicate the tumors (e.g. blockade of cytotoxic
T lymphocytes and increasing the expansion and activation
of effector T cells). Recently, numerous biological agents have
been approved for clinical practice, being even more under
development [10]. One of the highest selling classes of biolo-
gicals since 2009 is the monoclonal antibodies [11]. Indeed,
they gathered significant attention due to their high specificity
and potency [12].
Gene therapy is based on the intentional modulation of
gene expression in specific cells by introducing exogenous
nucleic acids to induce the production of proteins (plasmid
deoxyribonucleic acid pDNA, complementary DNA cDNA,
messenger ribonucleic acid mRNA- and microRNA miRNA),
or to inhibit the transduction of harmful proteins (small inter-
fering RNA siRNA- or antisense oligonucleotides) [13,14].
There are two different approaches to deliver nucleic acids
to the targeted tissues: direct (using viral or non-viral vectors)
or transduced cell-mediated (by in vitro genetic manipulation
of cells). Even though in recent years, a vast number of
therapeutic gene approaches have demonstrated effective-
ness in preclinical models, only a few have moved forward
into clinical trials [15].
Despite the significant advancements in the treatment of
bone and cartilage diseases, they still present low efficiency
and severe side effects. To overcome these limitations, differ-
ent strategies of drug delivery are currently used in the clinical
practice. By definition, drug delivery refers to a method or
process of administering a pharmaceutical compound to
safely achieve its desired therapeutic effect [16]. These strate-
gies are designed to alter the pharmacokinetic and/or biodis-
tribution of their associated drug, to function as their reservoir,
or both. Preclinical and clinical studies are exploring a variety
of drug delivery systems (DDS), such as nanoparticles (NPs),
microparticles (MPs), micelles, dendrimers, liposomes, hydro-
gels and scaffolds (Figure 1), which have been slowly trans-
lated into the clinical practice.
In this review, we discuss the recent advances in the devel-
opment of several drug delivery strategies based on biode-
gradable polymers for treating bone and cartilage diseases.
First, different strategies are introduced and systematized.
Then, recent advances including new therapeutic drugs,
novel targeting approaches, and innovative delivery vehicles
are highlighted for each condition. Finally, to enable those
systems to reach the clinical practice, an expert opinion of
the challenges and future directions is given.
2. Drug delivery by biodegradable polymers
networks
Two concepts introduced in the 19
th
and in the 20
th
centuries
have been revolutionizing the medical field, namely the magic
bullet and nanotechnology. The first concept was coined to
Article highlights
The treatment of bone and cartilage diseases remains an unmet
medical need despite the efforts to develop effective and innovative
strategies.
Novel drugs (e.g. chemical substances and biological drugs), innova-
tive tools (e.g. nanotechnology and 3D printing), and smart drug
delivery devices (e.g. stimuli-responsive biomaterials) can lead to
a revolution in the current available treatments.
In addition to passive targeting, drug delivery systems can be
advanced by their functionalization with targeting moieties specific
for bone or cartilage tissues.
Drug loading and releasing from tissue engineering approaches can
modulate and enhance tissue repair.
Clinical translation of promising treatments has been hindered mainly
due to the poor correlation between pre-clinical and clinical results.
This box summarizes the key points contained in the article.
Figure 1. Schematic illustration of the various drug delivery systems used in
bone and cartilage diseases.
2 A. C. LIMA ET AL.

Paul Ehrlich, in 1900, and is related to a limited effect of the
drugs on the cellular target [17]. Therefore, the linking of
a targeting moiety to a drug will increase its therapeutic
index. Biodegradable polymers are frequently used as carriers
in those strategies. Moreover, the assembling of this concept
to nanotechnology has provided significant progress in the
diagnostic, treatment and prevention of human diseases. The
term nanotechnology has been assigned to Richard Feynman,
in 1959 [18], but Norio Taniguchi was the first scientist to use
that word at 1974 [19]. Nanotechnology embraces The design,
characterization, production, and application of structures,
devices, and systems at the nanometre scale [20], with at
least one novel/superior characteristic or property [21].
Although the International Organization for Standardization
(ISO/TS 80,0041:2015) defines nanoscale as the length
range approximately from 1 nm to 100 nm, there is consider-
able controversy among the scientific community especially
for the upper limit. Indeed, a straight relationship between
size and novel effects or functions for different materials does
not exist [22]. Therefore, despite the nanoscale definition, in
the literature nanostructures frequently include sub-micron
particles (1 nm to 1000 nm). The drug delivery field has
been advanced and reinforced mainly due to the develop-
ment of novel and innovative technologies, and the remark-
able increase of knowledge about materials science and
pathophysiology, biomarkers and targets of the diseases.
With an appropriate DDS it is possible to circumvent impor-
tant drawbacks of the conventional therapies, namely (i) to
decrease the dose of drug administered (by avoiding its meta-
bolism/degradation, clearance and distribution in non-target
tissues), (ii) to abolish or drastically reduce the systemic side
effects (by targeting delivery, which will enhance the pharma-
cokinetics and pharmacodynamics of the drug, and conse-
quently will increase its therapeutic index) and (iii) to reduce
the frequency of administration (by the sustained release of
therapeutic concentrations of the drug over time). Therefore,
an appropriate delivery system can recover withdrawn drugs
from the market by overcoming their side effects in non-target
tissues/organs [23,24].
A rational design of a delivery system should consider the
nature of the drug to be incorporated (e.g. hydrophobic, hydro-
philic or amphipathic), the mechanisms that will control its
release (e.g. diffusion, carrier degradation or dissolution, clea-
vage of chemical bonds, and external, physiological or patholo-
gical stimulus) and the disease (e.g. cell/tissue to target or tissue
pH and vascularization). Ideally, the drug must be incorporated
into the delivery device, being released only in the target cells or
tissues in concentrations within the therapeutic range.
Moreover, depending on the mechanism of action of the ther-
apeutic agents (e.g. binding to a cell membrane receptor or to
an intracellular or nuclear target), the design of delivery carriers
should be carefully considered. The selection of the most ade-
quate composition is crucial to obtain DDS with the desirable
drug release properties. Additionally, the preparation method as
well as the physico-chemical properties of the delivery device
(e.g. size and degradation rate in the biological environment)
will also influence the release of the drugs [25]. Efforts were also
made to achieve a drug release in a pulsatile fashion, triggered
by changes in the neighboring milieu (self-regulated delivery
systems using different mechanisms, such as pH-sensitive poly-
mers, enzymes, illness markers and pH-dependent drug solubi-
lity) or by an external stimulus (externally triggered systems by
a magnetic, thermal, ultrasonic, electric or irradiation stimulus)
[2628]. Among the wide variety of natural, semisynthetic or
synthetic materials that can be used to produce DDS, biode-
gradable polymers (e.g. proteins, polysaccharides, poly(amino
acids) and polyesters) [29] have been preferred to produce
innovative, effective and specialized release dosage forms, due
to their advantages (e.g. avoiding body accumulation and pre-
dictable degradation). For instance, the synthetic polymers, poly
(lactic-co-glycolic acid) (PLGA) and poly(ε
-caprolactone) (PCL),
an
d the natural polymers chitosan, hyaluronic acid, alginate
and albumin are widely used for the preparation of polymeric
NPs (11000 nm in size) and MPs (11000 µm) [30,31]. NPs and
MPs are collective terms for both nano/microspheres and nano/
microcapsules (Figure 1). Nano/microspheres have a compact
matrix structure and the drugs can be entrapped, dispersed,
dissolved within the polymer matrix or adsorbed at their sur-
faces [32]. For nano/microcapsules, as they are vesicular systems
with a hollow liquid core surrounded by a polymeric membrane,
besides the referred locations, the drugs can also be encapsu-
lated in that core [32]. Biodegradable polymers can also be used
to produce other DDS, namely micelles and dendrimers (Figure
1). Polymeric micelles are produced from amphiphilic copoly-
mers that self-assemble in nanostructures ( 10200 nm in size)
[33,34]. Dendrimers ( 210 nm in diameter) are highly
branched polymeric structures with enhanced functionality,
due to the presence of several functional groups at their surface
[35,36].
The association of polymers to other biodegradable materials,
such as lipids, can be performed to improve their properties. For
instance, the binding of polyethylene glycol (PEG) to liposomes
(phospholipid bilayers with sizes ranging from 30 nm to several
µm [37,38]) is widely used to increase their residence time in
circulation. Moreover, lipidpolymer hybrid NPs were developed
to overcome the limitations and combine the advantages of
both polymeric NPs and liposomes, leading to more robust
DDS in terms of stability and controlled release, for instance [39].
To repair the function and structure of damaged or diseased
bone and/or cartilage, the implantation of 3D-engineered struc-
tures (e.g. scaffolds or hydrogels) loaded with drugs encapsu-
lated or not in DDS may be more effective. Indeed, due to the
limited intrinsic ability to repair of cartilage as well as of bone in
elderly patients or in the presence of large defects or congenital
abnormalities, tissue engineering approaches may be preferred.
2.1. Targeting strategies
The target delivery of a drug can be either passive or active.
Passive targeting is widely investigated mainly in cancer and
inflammatory conditions, due to the leaky vasculature or
enhanced permeability and retention (EPR) effect [40]. For
this and for many other features (e.g. drug release and inter-
action with cells [30]), the size as well as the surface and shape
of the delivery systems are crucial. Active targeting is achieved
by attaching to the drug or to the surface of the delivery
devices a particular ligand that ideally will bind to a moiety
EXPERT OPINION ON DRUG DELIVERY 3

specifically found in a specific organ, tissue or cell of interest
(Figure 2).
2.1.1. Bone and cartilage targeting
The peculiarity of the bone and cartilage structures difficult the
attainment of drug concentrations required to elicit the desired
biological response at the cell and matrix targets. Therefore,
there is a huge interest in designing drug delivery strategies to
selectively target bone or cartilage diseased areas delivering the
drug where its therapeutic action is required.
In bone, drug-targeting strategies take advantage of its high
content of hydroxyapatite and of the existence of specific cells
[41,42]. Therefore, the following moieties are usually used for
bone targeting:
(1) Bisphosphonates (BPs) have been widely used for drug
delivery into bone, due to their affinity for hydroxyapa-
tite. They are chemically stable derivatives of the natu-
rally occurring inorganic pyrophosphate. Besides being
a bone-binding class of molecules (e.g. clodronate, eti-
dronate, alendronate, risedronate, and zoledronate),
BPs are also used to treat bone diseases characterized
by an imbalance between osteoblast-mediated bone
formation and osteoclast-mediated bone resorption,
such as osteoporosis, Paget disease, vascular calcifica-
tion or bone metastasis [43,44].
(2) Tetracyclines are broad-spectrum antibiotics used to
treat several gram-positive and gram-negative bacterial
infections [45] and as bone-targeting moieties due to
their ability to bind specifically to hydroxyapatite [46
48]. Indeed, these bone-targeting moieties have been
used in bone histomorphometry as new bone forma-
tion markers [49,50]. They were the first drugs used as
bone-targeting agents, but their use is decreasing
mainly due to their poor stability after conjugation.
Moreover, as tetracyclines have the ability to inhibit
collagenases and other matrix metalloproteinases
(MMPs), they can inhibit the degradation of collagen I,
the main organic component of connective tissues such
as bone. Besides inhibiting bone loss, they can also
increase bone formation, because of the pro-anabolic
and anti-catabolic properties that these drugs present
[49,51].
(3) Oligopeptides containing acidic amino acids have high
affinity toward hydroxyapatite [5255], being an attrac-
tive option due to their lack of adverse effects [42].
Despite the exact mechanism is currently under debate,
it is known that the affinity of peptides to hydroxyapatite
increases when repeating units of Aspartic acid (Asp) or
Figure 2. Examples of targeting moieties used in drug delivery systems to treat bone and cartilage diseases.
4 A. C. LIMA ET AL.

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Journal ArticleDOI
TL;DR: The burden of four major musculoskeletal conditions: osteoarthritis, rheumatoid arthritis, osteoporosis, and low back pain, which affects nearly everyone at some point in time and about 4-33% of the population at any given point is described.
Abstract: Musculoskeletal conditions are a major burden on individuals, health systems, and social care systems, with indirect costs being predominant. This burden has been recognized by the United Nations and WHO, by endorsing the Bone and Joint Decade 2000-2010. This paper describes the burden of four major musculoskeletal conditions: osteoarthritis, rheumatoid arthritis, osteoporosis, and low back pain. Osteoarthritis, which is characterized by loss of joint cartilage that leads to pain and loss of function primarily in the knees and hips, affects 9.6% of men and 18% of women aged > 60 years. Increases in life expectancy and ageing populations are expected to make osteoarthritis the fourth leading cause of disability by the year 2020. Joint replacement surgery, where available, provides effective relief. Rheumatoid arthritis is an inflammatory condition that usually affects multiple joints. It affects 0.3-1.0% of the general population and is more prevalent among women and in developed countries. Persistent inflammation leads to joint destruction, but the disease can be controlled with drugs. The incidence may be on the decline, but the increase in the number of older people in some regions makes it difficult to estimate future prevalence. Osteoporosis, which is characterized by low bone mass and microarchitectural deterioration, is a major risk factor for fractures of the hip, vertebrae, and distal forearm. Hip fracture is the most detrimental fracture, being associated with 20% mortality and 50% permanent loss in function. Low back pain is the most prevalent of musculoskeletal conditions; it affects nearly everyone at some point in time and about 4-33% of the population at any given point. Cultural factors greatly influence the prevalence and prognosis of low back pain.

3,133 citations


"Biodegradable polymers: an update o..." refers background in this paper

  • ...Bone and cartilage-related diseases affect the musculoskeletal system and function, leading to a significant burden over the global public health and economy [1]....

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Posted Content
Cristina Buzea1, Ivan Pacheco1, Kevin Robbie1Institutions (1)
Abstract: This review is written with the goal of informing public health concerns related to nanoscience, while raising awareness of nanomaterials toxicity among scientists and manufacturers handling them. We show that humans have always been exposed to nanoparticles and dust from natural sources and human activities, the recent development of industry and combustion-based engine transportation profoundly increasing anthropogenic nanoparticulate pollution. The key to understanding the toxicity of nanoparticles is that their minute size, smaller than cells and cellular organelles, allows them to penetrate these basic biological structures, disrupting their normal function. Among diseases associated with nanoparticles are asthma, bronchitis, lung cancer, neurodegenerative diseases (such as Parkinson`s and Alzheimer`s diseases), Crohn`s disease, colon cancer. Nanoparticles that enter the circulatory system are related to occurrence of arteriosclerosis, and blood clots, arrhythmia, heart diseases, and ultimately cardiac death. We show that possible adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, and agglomeration state. The faster we will understand their causes and mechanisms, the more likely we are to find cures for diseases associated with nanoparticle exposure. We foresee a future with better-informed, and hopefully more cautious manipulation of engineered nanomaterials, as well as the development of laws and policies for safely managing all aspects of nanomaterial manufacturing, industrial and commercial use, and recycling.

2,392 citations


Performance
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No. of citations received by the Paper in previous years
YearCitations
20217
20207
20161
19621